Dr. Renaud La Joie originally trained in Neuroscience, Neuropsychology, and Neuroimaging in Caen, France before moving to California for his post-doctoral fellowship at UC Berkeley and then at UCSF. In his research, he combines multimodal neuroimaging techniques, fluid biomarkers, and neuropsychological measures to study the natural history of Alzheimer’s disease and other age-associated neurodegenerative diseases. He has established strong collaborations with neuropathologists to help bridge in vivo and post-mortem measures of brain pathology and guide a rigorous interpretation of in vivo biomarker data. His overarching goal is to understand the drivers of clinical heterogeneity and improve our ability to provide patients with a precise diagnosis and prognosis. Dr La Joie’s research is supported by the Alzheimer’s Association, NIA/NIH, and the US department of defense. His work has been awarded the de Leon award in neuroimaging, and the Christopher Clark at the Human Amyloid Imaging Conference.

Abstract

Patients with sporadic early-onset Alzheimer’s disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, common non-amnestic presentations, or absence of pathogenic mutations. To fill in this gap in knowledge, the multi-center Longitudinal Early onset Alzheimer’s Disease Study (LEADS) was launched in 2018; data acquisition is similar to the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to allow a direct comparison to late-onset AD. In this presentation, I will summarize the findings from the first 525 patients.

As of July 2024, 23% of patients with a clinical diagnosis of early-onset MCI or AD dementia included in LEADS are amyloid-PET positive. These patients have high tau-PET levels, which strongly correlates with clinical severity and clinical phenotypes (e.g. amnestic, language predominant, …). Importantly, patient with EOAD have higher tau-PET burden than their older-onset counterparts from the ADNI cohort, even when matching on clinical stage and amyloid-PET levels.

LEADS includes annual visits with clinical, cognitive, MRI, and PET examinations for 4 years. Available data suggests that both amyloid and tau-PET are dynamic in patients with MCI and dementia, with significant increases over time in both modalities. Yet, regional variability is important for tau-PET: accumulation in the frontal lobe immediately precedes cognitive decline and tracks closely with clinical progression, while temporoparietal tau-PET is prominent at clinical onset and plateaus as dementia worsens.

Amyloid-PET-negative patients, aka patients who were clinically diagnosed with EOAD but do not have PET evidence for underlying AD are a very heterogeneous group. Using FDG-PET to characterize different subgroups, we identified that 52% of these patients have a normal FDG scan, suggestive of non-degenerative conditions or very early disease stages; this group have elevated rates of depressive symptoms and sleep apnea. The other half of amyloid-negative patients have significant hypometabolism but various regional patterns can be found, suggestive of Lewy Body Disease or Fronto-Temporal Lobar Degeneration subtypes.

Finally, I will discuss new developments in the LEADS cohort, including the inclusion of patients receiving anti-amyloid therapies as part of their clinical care, and the upcoming inclusion of additional LEADS sites in Europe and Latin America.